Matrix-induced autologous chondrocyte implantation (mACI) versus autologous matrix-induced chondrogenesis (AMIC) for chondral defects of the knee: a systematic review

Abstract Introduction Chondral defects of the knee are common and their treatment is challenging. Source of data PubMed, Google scholar, Embase and Scopus databases. Areas of agreement Both autologous matrix-induced chondrogenesis (AMIC) and membrane-induced autologous chondrocyte implantation (mACI) have been used to manage chondral defects of the knee. Areas of controversy It is debated whether AMIC and mACI provide equivalent outcomes for the management of chondral defects in the knee at midterm follow-up. Despite the large number of clinical studies, the optimal treatment is still controversial. Growing points To investigate whether AMIC provide superior outcomes than mACI at midterm follow-up. Areas timely for developing research AMIC may provide better outcomes than mACI for chondral defects of the knee. Further studies are required to verify these results in a clinical setting.


Introduction
Hyaline cartilage tissue is alymphatic and hypocellular, with low metabolic activity and limited regenerative capabilities. [1][2][3] The healing process of chondrocytes often does not result in restitutio ad integrum, and residual chondral defects or a fibrotic scar are frequent. 4 ,5 Focal chondral defects of the knee are debilitating, leading to marked decline in quality of life and, in athletes, a high chance of retirement from sport. 6 ,7 Conservative strategies are often not adequate to manage focal chondral defects of the knee. 8,9 Thus, surgical management is often required. 10,11 Several different surgical strategies have been proposed to manage focal chondral defects of the knee. [12][13][14] After its introduction, membrane-induced autologous chondrocyte implantation (mACI) has been broadly performed. 11,15,16 In 2005, Behrens 17 first described an enhanced microfractures technique, which quickly evolved into the autologous matrix-induced chondrogenesis (AMIC) procedure. Given its simplicity, AMIC quickly gained the favour of surgeons and patients. 18 To the best of our knowledge, no previous study compared these two strategies in a clinical setting for chondral defect of the knee. AMIC was supposed to perform better than the mACI procedure; however, no consensus has been reached, and updated evidenced-based recommendations are required. Thus, a systematic review was conducted to investigate whether AMIC provides better outcomes than mACI for knee chondral defects at midterm follow-up. This study focused on patient-reported outcome measures (PROMs) and complication rates. We hypothesized that AMIC and mACI procedures provided equivalent clinical outcome.

Search strategy
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 19 The PICO algorithm was preliminarily stated:

Data source and extraction
The literature search was conducted by two authors (Filippo Migliorini1 and Jörg Eschweiler) separately in January 2022. The following databases were accessed: PubMed, Google scholar, Embase and Scopus. The following keywords were used in combination: chondral, cartilage, articular, damage, defect, injury, chondropathy, knee, pain, matrixinduced, autologous, chondrocyte, transplantation, implantation, mACI, AMIC, therapy, management, surgery, outcomes, hypertrophy, failure, revision, reoperation, recurrence. The same authors independently screened the resulting articles from the search. The full-text of the articles of interest was accessed. A cross-reference of the bibliographies was also performed. Disagreements between the two authors were solved by a third author (Nicola Maffulli).

Eligibility criteria
All the studies investigating the outcomes of AMIC and/or mACI for knee chondral defects were accessed. Given the authors language abilities, articles in English, Italian, French, Spanish and German were eligible. Levels I to IV of evidence studies, according to the Oxford Centre of Evidence-Based Medicine, 20 were suitable. Only studies investigating a minimum of five patients were included. Abstracts, reviews, letters, opinion, editorials and registries were excluded. Biomechanics, animals or in vitro studies were not considered. Only studies that used a cell-free bioresorbable membrane were considered. Studies augmenting AMIC or mACI with less committed cells (e.g. bone marrow concentrate, mesenchymal stem cells) or grow factors were not considered. Studies involving patients with kissing lesions were not included, nor were those involving patients with end-stage osteoarthritis. Only studies that clearly stated the duration of the follow-up were eligible. Only studies which reported quantitative data with regards to the outcomes of interest were included in this study.

Data extraction
Data extraction was conducted independently by two authors (Filippo Migliorini1 and Jörg Eschweiler). Generalities of the included studies (author and year, journal, study design) and patients demographic at baseline were collected (length of symptoms prior of treatment, number of procedures, mean body mass index (BMI) and age of the patients, length of the follow-up, gender, mean defect size). For each of the two techniques, the following data were retrieved: Visual Analogue Scale (VAS), Tegner Activity Scale, 21 International Knee Documentation Committee (IKDC) 22 and the Lysholm Knee Scoring Scale. 23 Data regarding the following complications were also collected: rate of hypertrophy, failures, revision surgeries and total knee arthroplasty. The recurrence of symptomatic chondral defects which affect negatively the patient quality of life was considered as failure.

Methodology quality assessment
The methodological quality assessment was accomplished by two independent authors (Filippo Migliorini1 and Jörg Eschweiler). The risk of bias graph tool of the Review Manager Software (The Nordic Cochrane Collaboration, Copenhagen) was used. The following risks of bias were evaluated: selection, detection, attrition, reporting and other sources of bias.

Statistical analysis
The statistical analysis was performed with IBM SPSS Version 25. Continuous data were reported as mean difference (MD), while binary data were evaluated using the odd ratio (OR) effect measure. The confidence interval (CI) was set at 95% in all the comparisons. T-test and χ 2 were evaluated for continuous and binary data, respectively, with P < 0.05 considered statistically significant.

Search result
A total of 503 articles were initially obtained and 107 were excluded as they were duplicates. A further 349 articles were excluded because they did not match the inclusion criteria: not focused on mACI or AMIC (N = 225), not focusing on knee (N = 37), study design (N = 51), not reporting quantitative data under the outcomes of interest (N = 12), combined with other committed cells (N = 12), other (N = 8), language limitations (N = 3), not clearly stating the duration of the follow-up (N = 1). Finally, 47 articles were available for this study. The results of the literature search are shown in Figure 1.

Methodological quality assessment
As 27% (12 of 45) of the investigations were randomized clinical trials, and 20% (9 of 45) were retrospective studies, the risk of selection bias of random sequence generation was moderate. The overall risk of selection bias of allocation concealment was low. Given the overall lack of blinding, detection bias was moderate-high. The risk of attrition and reporting bias across all included studies was low, as was the risk of other bias. In conclusion, the risk of bias was moderate, attesting to this study acceptable methodological assessment (Fig. 2).

Patient demographics
Data from 1667 procedures were retrieved; 36% (600 of 1667 patients) were women. The mean follow-up was 37.9 ± 21.7 months. The mean age of the patients was 34.7 ± 6.5, and the mean BMI 25.5 ± 1.6 kg/m 2 . The mean defect size was 3.9 ± 1.2 cm 2 . Generalities and demographics of the study are shown in Table 1.
Good comparability was found between the two groups at baseline ( Table 2).

Discussion
According to the main findings of the present systematic review, AMIC performed better than mACI for chondral defects of the knee at ∼40 months followup. The rate of complications was noticeably lower in the AMIC group. While the Tegner and VAS scores were similar, the mean difference of the Lysholm and IKDC scales exceeded the minimally clinically important difference (MCID) in favour of the AMIC group. 21 ,24 mACI has been largely performed in patients with focal chondral defects of the knee. 25,26 For the mACI procedure, an arthroscopy of the knee is performed first to assess cartilage status, identify the chondral defect and harvest chondrocytes from a non-weightbearing zone of the distal femur. [27][28][29] Autologous chondrocytes are subsequently extracted and cultivated, and expanded in vitro for ∼3 weeks, over a membrane that acts as medium for cell proliferation. 30,31 In a second-step surgery, the defect is debrided and the membrane is secured into the defect. 32,33 The current literature presents several clinical trials reporting the surgical outcomes of mACI. However, there are still controversies. The optimal surgical approach, whether arthrotomy, mini-arthrotomy or arthroscopy, has not been clarified. Additionally, there are several different membranes used for expansion (resorbable cell-free or cell-based, synthetic), and the most appropriate type of fixation (suture or fibrin glue) is still unclear. [34][35][36][37][38][39] Recently, AMIC has gained increasing interest. 36,[40][41][42][43] Differently from mACI, which uses laboratory expanded autologous chondrocytes, AMIC is a single session procedure which exploits the regenerative potential of bone marrow derived mesenchymal stem cells (BM-MSCs). 14,44 After defect debridement and curettage, microfractures are performed. 45,46 A membrane is then placed into the defect. BM-MSCs from the subchondral layer migrate into the membrane and regenerate the hyaline cartilage layer. 12,47,48 Similar to mACI, AMIC can be performed through arthrotomy, miniarthrotomy or arthroscopy. 49 ,50 However, AMIC is more cost-effective, since it requires only one surgical step, avoiding in vitro cell expansion. Moreover, along with the avoidance of chondrocyte harvesting, AMIC should lead to less morbidity and faster recovery. These features make AMIC attractive to both surgeons and patients. We were unable to identify clinical studies which directly compare AMIC versus mACI for chondral defects of the knee:    We point out that all statistical analyses were performed regardless of the surgical approach. Indeed, authors performed the procedures using arthrotomy, mini-arthrotomy or arthroscopy. The mACI cohort included a larger number of studies and related procedures compared with the AMIC group. This discrepancy may generate biased results and influence the rate of uncommon complications related to poorer outcome. Given the lack of quantitative data, the average return to daily activities and/or sport participation were not investigated. All the membranes considered in the present investigation were cell-free and bioresorbable (collagenic or hyaluronic): this study did not consider cellbased or more innovative synthetic scaffolds. [51][52][53][54][55][56][57][58][59] Moreover, the typology of membrane fixation (fibrin glue, suture, both methods or no fixation) was not considered as separate. Given the lack of relevant data, it was not possible to overcome these limitations. Many authors did not differentiate between primary and revision settings, and several studies included patients who received combined surgical procedures. Two studies 60 ,61 performed membraneassisted autologous chondrocyte transplantation (mACT). In mACT procedures, chondrocytes are harvested, cultivated and expanded into a membrane in the same fashion of mACI. The chondrocyteloaded membrane is then carefully implanted into the defect using custom-made instruments in a fullarthroscopic fashion. 62 ,63 Given these similarities, we analysed mACT and mACI as a single entity. The lack of detailed information did not allow us to analyse the aetiology of chondral defects as separate data sets. These limitations suggest cautious interpretation of the conclusions of this study.

Conclusion
AMIC may provide better outcomes than mACI for chondral defects of the knee. Further studies are needed to validate these results in a clinical setting.

Conflict of interest statement
The authors have no potential conflicts of interest.

Funding
No external source of funding was used.

Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent
For this type of study informed consent is not required.

Data availability
The data underlying this article are available in the article and in its online supplementary material.